Résumé

The ability of hematopoietic stem/progenitor cells (HSPCs) to respond to infections by expanding myeloid cells plays an important role in host defense. Although the mechanism of parasite-induced immune response has been extensively studied in the spleen and liver in mice, little is known about the effect of parasite expansion on HSPC function and differentiation in bone marrow (BM). Leishmania donovani parasites infect host macrophages, not HSPCs, but they do establish chronic infection in the BM. Here, we show a gradual increase in HSPC numbers in BM and spleen. During the chronic phase, HSPCs showed a bias towards myeloid differentiation with reduced numbers of BM B cells and an accumulation of myeloid cells in the spleen and liver. Enhanced cell cycle progression and expansion of HSPCs were accompanied by an increase in β-catenin activation over the course of infection, suggesting a role for Wnt/Frizzled (Fzd) signaling in HSPC activation in Leishmaniasis. To investigate the importance of Wnt-associated HSPC activation, we used Fzd6-/- mice whose HSPCs respond poorly to LPS-induced inflammation. Fzd6-/- HSPCs generated fewer granulocyte-monocyte progenitors and consequently fewer Ly6Chi monocytes. Fzd6-/- BM Ly6Chi monocytes expressed high levels of CCR2 suggesting that they were released normally from the BM. However, their numbers were strongly decreased in the Fzd6-/- spleen as compared to the controls. This decrease in myeloid differentiation correlated with a decrease in parasite expansion, as measured by reduced splenic burden, probably due to a corresponding decrease in monocyte-derived macrophages, which are the principal target of the parasite. Our results suggest an important role for Wnt/Fzd-dependent HSPC activation in regulating Leishmania donovani infection.